In this issue of TRANSFUSION, Reems et al.1 report on their experience with the process of applying for an Investigational New Drug (IND) application related to the operation of an umbilical cord blood bank. The IND process may not be familiar to many transfusion medicine practitioners, and this editorial will discuss some of the basic aspects of this regulatory mechanism.
The IND, unlike a Biologics License Application (BLA) or a New Drug Application (NDA), is not a permit to market a product in interstate commerce. Rather, it is an exemption from the federal regulation that prohibits an unapproved biologic from being shipped in interstate commerce. “IND” is synonymous with “Notice of Claimed Investigational Exemption for a New Drug.” An investigational new drug, for which an IND application is in effect, is exempt from premarketing approval requirements that are otherwise applicable, and the drug may be shipped lawfully for the purpose of conducting clinical investigation of that drug. The sponsor, who takes responsibility for and initiates a clinical investigation, may be an individual, a pharmaceutical company, a government agency, an academic institution, a private organization, or other organization. The fundamental regulations underlying INDs for drugs and biologics are quite similar, as are those for medical devices, although, for devices, the application is an Investigational Device Exemption.
The above language was extracted largely from the pertinent regulatory section, 21 CFR 312. That section also contains a list of the essential elements of an IND application, beginning with the cover sheet, Form FDA [Food and Drug Administration]-15 71, and including a General Investigational Plan, an Investigator's Brochure, Clinical Protocols, and data on the drug and its method of manufacture. Rather than reading an explanation of these, it might be of greater interest to the readers of TRANSFUSION to consider in more general terms the purpose of the IND and the nature of the review and monitoring processes.
At the outset, it is important to emphasize that a sponsor files an IND application for a specific product. If a product has not been defined, there is no basis for an IND application. A sponsor with an idea that he wishes to market for clinical use must first develop the idea into a concrete product for which specifications can be written, before that sponsor can approach the FDA with an IND application. Once that goal has been reached, the sponsor can describe the pharmacology and toxicology of the product, the methods used to manufacture it, the clinical use for the product (the “indication”), and the plans for conducting testing that will support approval of the product for that indication. All this is accommodated within the format for an IND application that is described in 21 CFR 312 and in guidance documents available from the FDA.
Because the sponsor will be proposing to test an unapproved product on human subjects, the welfare of the subjects must be guarded, and this is the principal concern of the FDA in the IND process. The FDA will require sufficient data on the nature of the product to ensure the safety of the subjects, in accord with a risk-benefit analysis that is appropriate to the product and the clinical indication. A minor modification in a red cell storage solution should present very little risk to test subjects (because current red cell solutions are quite safe and effective), while a new therapy for lymphoma might carry considerable risk along with the potential to aid in the therapy of this usually fatal disease. Procedures to be used for obtaining informed consent from the study subjects are an important part of the IND application. Central to the application is the plan for the study itself, described in the study protocol. The protocol is a description of the study, directions for conducting the study, and a plan for analysis of the data.
The FDA will expect less detail and specificity about the product and the clinical studies in the early stages of investigation, Phase I (safety studies) and early Phase II (activity and dosage studies). As the investigation progresses, the FDA will want more complete information about the pharmacology and toxicology of the product and about the clinical studies to be conducted. In practice, this means that a sponsor with a product that requires a basic test in humans before further development can progress might apply for a “feasibility” or “proof of concept” study. Suppose, for example, that a sponsor has a new product intended to inactivate viruses in red cells, but is not certain of the effect of the product on red cell survival in humans. If satisfactory toxicology data can be provided, it is likely that the FDA will approve a small clinical study, using low volumes of treated and labeled autologous red cells, to determine whether this product is a candidate for further development. If the data are favorable, the FDA will then want to see more detailed information about product properties, manufacture, and intended clinical indication(s). The sponsor will then be required to present a very specific protocol for a pivotal clinical study that will produce the data to support the application for marketing.
Many sponsors will request a pre-IND meeting with the FDA to obtain answers to questions that arise early in the course of product development. Such meetings are not required, but are especially helpful for both the FDA and the sponsor when the proposed IND involves novel products or concepts. When the IND application is submitted to the FDA's Center for Biologics Evaluation and Research, it is sent to a group of reviewers who will evaluate the technical (microbiology, molecular biology, transfusion, statistics, etc.), medical, and administrative aspects of the application. The reviewers will meet to discuss the application and the sponsor will be informed, within 30 days, whether or not the proposed clinical study may begin. If the reviewers find some very specific defects in the application (e.g., human subjects might be exposed to unreasonable risk, clinical investigators are not qualified, or the application does not contain sufficient information to assess the risks to the subjects), the application will be put on “clinical hold” until the sponsor can adequately address the deficiencies. Once the application has received approval, the studies may begin. The sponsor will then be obliged to file a number of reports to the FDA: protocol amendments, safety reports, and annual reports. During the course of an IND, the interaction between the sponsor and the FDA is an active one.
There are several types of INDs. The type encountered most frequently is the “commercial IND”; this is an application submitted by a sponsor whose ultimate goal is to obtain marketing approval for a new product. There are also “noncommercial INDs.” A type that is seen most often with pharmaceuticals is the “research IND,” submitted by physicians who cross-reference the master IND of a pharmaceutical firm and who study specific, new indications for a drug. The “treatment IND” is a special case that permits the sponsor to recover costs during the development period. This mechanism was used in the development of several new AIDS-related drugs. A treatment IND has a number of characteristics: drugs that are in controlled clinical trials can be provided outside these trials to treat patients with serious or immediately life-threatening diseases for which no comparable or satisfactory alternative therapy exists; full informed consent must be obtained from patients; the drug cannot be promoted or otherwise commercialized; the main clinical trials must continue; and the sponsor must pursue marketing approval with due diligence. Finally, there is the “emergency-use IND,” formerly known as the “compassionate IND.” This mechanism is used to obtain an experimental agent for a seriously ill patient who cannot be enrolled in an existing protocol, for example, because he or she cannot be transported to a study site or does not precisely qualify for the protocol in use. The sponsor and the FDA must agree to such emergency use, and the sponsor must provide the FDA with required data on the product and on the patient after the treatment has been completed.
In summary, the IND application is a regulatory mechanism that permits the biomedical community and the FDA to work together to protect the rights and safety of study subjects who participate in clinical trials that will provide the next generation of diagnostic and therapeutic agents.
Joseph C. Fratantoni, MD1 1Vice-President Biologics C.L. McIntosh & Associates Rockville, MD 20851
